分子动力学洞察多胺-DNA结合模式：交联选择性的含义。,Chemistry - A European Journal

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分子动力学洞察多胺-DNA结合模式：交联选择性的含义。
Chemistry - A European Journal ( IF 3.9 ) Pub Date : 2017-08-16 , DOI: 10.1002/chem.201702065
Emmanuelle Bignon _{1,

2} , Chen-Hui Chan ₂ , Christophe Morell ₁ , Antonio Monari _{3,

4} , Jean-Luc Ravanat ₅ , Elise Dumont ₂

Affiliation

在DNA缩合和稳定中起作用的生物多胺无处不在，并在真核细胞核中以毫摩尔浓度发现。通过全原子显式溶剂分子动力学研究了三种多胺的相互作用模式，它们分别是：鸟氨酸（Put），精胺（Spm）和亚精胺（Spd），具有自互补的16个碱基对（bp）双链体。胺脂族链的长度导致相互作用模式从小沟槽结合变为大沟槽结合。通过全原子动力学，揭示了鸟嘌呤核苷的单电子氧化后，稳定多胺-DNA复合物并预示反应性的非共价相互作用，从而导致有害的DNA-多胺交联的低势垒形成。结合强度是通过分子力学广义Born表面积后处理（MM-GBSA）从获得的轨迹中量化的。结合自由能的值提供了与最近的等温量热法测定所确定的亲和力顺序Put <Spm <Spd相同的亲和力顺序，并具有令人满意的相关性，以验证结构预测。沿多胺系列的键合模式和碳氮距离说明了通过提取鸟嘌呤C8原子与铵基团之间的平均接近距离，对有害的DNA-多胺交联形成的选择性。这些结果表明，DNA-多胺交联的形成涉及鸟嘌呤自由基阳离子的去质子化以攻击多胺，

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Molecular Dynamics Insights into Polyamine–DNA Binding Modes: Implications for Cross‐Link Selectivity

Biogenic polyamines, which play a role in DNA condensation and stabilization, are ubiquitous and are found at millimolar concentration in the nucleus of eukaryotic cells. The interaction modes of three polyamines—putrescine (Put), spermine (Spm), and spermidine (Spd)—with a self‐complementary 16 base pair (bp) duplex, are investigated by all‐atom explicit‐solvent molecular dynamics. The length of the amine aliphatic chain leads to a change of the interaction mode from minor groove binding to major groove binding. Through all‐atom dynamics, noncovalent interactions that stabilize the polyamine–DNA complex and prefigure the reactivity, leading to the low‐barrier formation of deleterious DNA–polyamine cross‐links, after one‐electron oxidation of a guanine nucleobase, are unraveled. The binding strength is quantified from the obtained trajectories by molecular mechanics generalized Born surface area post‐processing (MM‐GBSA). The values of binding free energies provide the same affinity order, Put<Spm<Spd, as that determined by recent isothermal calorimetry measurements, with a satisfactory correlation, to validate the structural predictions. The binding modes and carbon–nitrogen distances along the series of polyamines illustrate the selectivity towards deleterious DNA–polyamine cross‐link formation through the extraction of average approaching distances between the C8 atom of guanines and the ammonium group. These results imply that the formation of DNA–polyamine cross‐links involves deprotonation of the guanine radical cation to attack the polyamines, which must be positively charged to lie in the vicinity of the B‐helix.

更新日期：2017-08-16

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